The objective of this research program is to study the conditions under which compensation and recovery of function occurs following experimentally induced neurodegeneration in the central nervous system(CNS). These studies employ neurotoxicants such as colchicine and excitotoxicants, such as N-methyl-D- aspartate, to destroy specific neuronal populations in the CNS. Studies focus on the hippocampus because of its well known cytoarchitecture and the fact that damage to this area evokes compensatory, functional and anatomical changes. Research has found that intrahippocampal administration of neurotoxicants evokes a series of pre-and postsynaptic changes in cholinergic systems in the hippocampus. These changes depend on the integrity of the septohippocampal pathway and are indicative of injury-induced reactive synaptogenesis in the hippocampus. Subsequent work has found injury- related changes in the signal transduction step for the cholinergic system. Future work will focus on the specificity of injury related effects on the signal transduction mechanism in the hippocampus and other regions of the CNS. The interaction between trophic factors and neurotransmitter-mediated turnover of phosphoinositides (PI) will also be studied, as well as the possible compensatory changes in PI turnover in other models of neurodegenerative disease. Research in this area aims to understand the more general process of synaptic plasticity that occurs following injury to the nervous system.